A partial trisomy of chromosome 5q11.2-q13.3, in unbalanced carriers of a chromosome rearrangement involving chromosomes 1 and 5 (der(1) inv ins (1;5)(q32.3;q13.3q11.2)), has been associated with neuroleptic responsive familial schizophrenia. This suggests that major gene lies within the q11.2-q13.3 region of chromosome 5 that when present in 3 copies predisposes to schizophrenia. The long term objectives of this project are to locate and identify a major gene that predisposes to schizophrenia. The specific aim is to delineate with molecular markers a chromosomal rearrangement that is associated with familial schizophrenia. It is planned to test whether a DNA molecular marker for the gene hexosaminidase B (Hex B), which is located at 5q13, lies within this trisomic region of chromosome 5. Dosage analysis of Southern blots of DNA isolated from members of this family will indicate whether the Hex B gene lies within the trisomic region of this rearrangement. It is also possible that this gene is within mapping distance of the breakpoint involved in this rearrangement regardless of whether it is contained within the trisomic region. This will be tested using pulse field gel electrophoresis of restriction digests cut with infrequent cutting enzymes that generate large fragments. Detection of the breakpoint is a necessary initial step for molecular isolation of the trisomic region. Genomic clones from the Hex B region will also be screened for restriction fragment length polymorphisms (RFLPs) in order to develop this region as a highly informative marker locus for linkage studies. This will enable testing of families with schizophrenia for the presence of a linked gene. The location of a linked gene in this region of chromosome 5 would be a first step toward isolation of the gene and characterization of its normal function. The clinical studies will consist of cytogenetic studies and psychiatric and neuropsychological evaluations of all available relatives of the proband. Structured interview schedules (Schedule of Affective Disorders and Schizophrenia SADS-L) will be used to assess for the presence of mental illness. These evaluations, using research criteria, will serve to confirm clinical observations that unaffected relatives are high functioning individuals with no history of mental illness or dysmorphic features and with no reason to suspect chromosomal abnormalities.